The development of resistance against chemotherapeutic agents is a major reason for the frequent failure in the clinical cancer therapy. Depending on the cancer cell-type, different molecular mechanisms counteract chemotherapeutic agents. The phrase Multi-Drug-Resistant (subsequently abbreviated as MDR) phenotype (S. Kuzmich et al., Med. Res. Rev. 1991, 11, 185) has been coined for a phenotype which has been selected for resistance to a single cytotoxic agent, but is found to exhibit cross-resistance to a variety of structurally and mechanistically unrelated compounds. The MDR-phenotype is observed upon treatment with vinca alkaloids, anthracyclines, and epipodophyllotoxins. A positive correlation exists between the MDR1-gene product P-glycoprotein of 170 KDalton molecular weight (subsequently abbreviated as P170) and the occurance of MDR (J. Bell, et al., Cancer Invest. 1991,9,563). P170 acts as an ATP-powered efflux-pump, which exports cytotoxic compounds from the endoplasm in a rather nonspecifc manner. In recent years, different classes of compounds were found to modulate MDR. Such compounds are: verapamil (E. Pommerenke et al., Arzneim.-Forsch. 1991, 41 (II), 855), niguldipine (A. Reymann et al., Arch.Pharmacol. 1991,343, Suppl. R50), cyclosporine A, and quinine (E. Solary et al., Cancer 1991, 68, 1714). As all of these compounds were developed for clinical applications other than MDR-modulation, they possess severe side effects (e.g. lowering blood pressure or suppression of the immune system). This makes it difficult to use the compounds as MDR-modulators in routine cancer therapy. Therefore, new modulators with reduced side effects or toxicity are required.
The present invention describes the preparation and use of 1-amino-3-phenoxy-propane-derivatives that are effective in modulating the resistance of tumor cells against chemotherapeutic agents like vincristine, vinblastine, adriamycine and etoposide.